rs2517951

Positions:

• chr17-39696844-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001289936.2(ERBB2):​c.-24+1663C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,098 control chromosomes in the GnomAD database, including 23,865 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.52 (23834 hom., cov: 30)
  • Exomes 𝑓: 0.50 (31 hom.)
• Consequence: ERBB2 NM_001289936.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.514

Genes affected

ERBB2 (HGNC:3430): (erb-b2 receptor tyrosine kinase 2) This gene encodes a member of the epidermal growth factor (EGF) receptor family of receptor tyrosine kinases. This protein has no ligand binding domain of its own and therefore cannot bind growth factors. However, it does bind tightly to other ligand-bound EGF receptor family members to form a heterodimer, stabilizing ligand binding and enhancing kinase-mediated activation of downstream signalling pathways, such as those involving mitogen-activated protein kinase and phosphatidylinositol-3 kinase. Allelic variations at amino acid positions 654 and 655 of isoform a (positions 624 and 625 of isoform b) have been reported, with the most common allele, Ile654/Ile655, shown here. Amplification and/or overexpression of this gene has been reported in numerous cancers, including breast and ovarian tumors. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

PGAP3 (HGNC:23719): (post-GPI attachment to proteins phospholipase 3) This gene encodes a glycosylphosphatidylinositol (GPI)-specific phospholipase that primarily localizes to the Golgi apparatus. This ubiquitously expressed gene is predicted to encode a seven-transmembrane protein that removes unsaturated fatty acids from the sn-2 position of GPI. The remodeling of the constituent fatty acids on GPI is thought to be important for the proper association between GPI-anchored proteins and lipid rafts. The tethering of proteins to plasma membranes via posttranslational GPI-anchoring is thought to play a role in protein sorting and trafficking. Mutations in this gene cause an autosomal recessive form of neurologic hyperphosphatasia with cognitive disability (HPMRS4). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERBB2	NM_001289936.2	c.-24+1663C>T		intron_variant			NP_001276865.1
ERBB2	NM_001005862.3	c.-18+1663C>T		intron_variant			NP_001005862.1
ERBB2	NM_001382782.1	c.-18+1663C>T		intron_variant			NP_001369711.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERBB2	ENST00000578199.5	c.-18+1663C>T		intron_variant		1		ENSP00000462808.1
ERBB2	ENST00000406381.6	c.-18+1663C>T		intron_variant		5		ENSP00000385185.2
ERBB2	ENST00000584601.5	c.-69+1663C>T		intron_variant		2		ENSP00000462438.1
PGAP3	ENST00000584856.1	c.-374G>A		upstream_gene_variant		4		ENSP00000463785.1

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79555 AN: 151724 Hom.: 23824 Cov.: 30

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.396

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.682

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.664

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.496 AC: 126 AN: 254 Hom.: 31 Cov.: 0 AF XY: 0.549 AC XY: 101 AN XY: 184

Gnomad4 AFR exome AF: 0.167

Gnomad4 AMR exome AF: 0.333

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.600

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.361

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.524 AC: 79580 AN: 151844 Hom.: 23834 Cov.: 30 AF XY: 0.524 AC XY: 38865 AN XY: 74190

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.534

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.396

Gnomad4 SAS AF: 0.669

Gnomad4 FIN AF: 0.682

Gnomad4 NFE AF: 0.664

Gnomad4 OTH AF: 0.548

Alfa AF: 0.578 Hom.: 4668

Bravo AF: 0.497

Asia WGS AF: 0.563 AC: 1958 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.79

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2517951; hg19: chr17-37853097;